NM_000459.5:c.2545C>T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_000459.5(TEK):c.2545C>T(p.Arg849Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000459.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TEK | NM_000459.5 | c.2545C>T | p.Arg849Trp | missense_variant | Exon 15 of 23 | ENST00000380036.10 | NP_000450.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TEK | ENST00000380036.10 | c.2545C>T | p.Arg849Trp | missense_variant | Exon 15 of 23 | 1 | NM_000459.5 | ENSP00000369375.4 | ||
TEK | ENST00000406359.8 | c.2416C>T | p.Arg806Trp | missense_variant | Exon 14 of 22 | 2 | ENSP00000383977.4 | |||
TEK | ENST00000519097.5 | c.2101C>T | p.Arg701Trp | missense_variant | Exon 13 of 21 | 2 | ENSP00000430686.1 | |||
TEK | ENST00000615002.4 | c.*1046C>T | 3_prime_UTR_variant | Exon 15 of 23 | 5 | ENSP00000480251.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152114Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251002Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135652
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461770Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727186
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152114Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74284
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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The TEK c.2545C>T; p.Arg849Trp variant (rs80338908) is reported in the literature segregating with disease in several large families affected with venous malformations (Shu 2012, Vikkula 1996). This variant is reported in ClinVar (Variation ID: 9293), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 849 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In vitro functional analyses show kinase activation leading to constitutive phosphorylation and suppression of apoptosis (Morris 2005, Vikkula 1996), and in vivo analyses of the variant protein demonstrate venous malformations in zebrafish (Du 2018). Based on available information, this variant is considered to be pathogenic. References: Du Z et al. Transgenic Expression of A Venous Malformation Related Mutation, TIE2-R849W, Significantly Induces Multiple Malformations of Zebrafish. Int J Med Sci. 2018 Feb 12;15(4):385-394. Morris PN et al. Functional analysis of a mutant form of the receptor tyrosine kinase Tie2 causing venous malformations. J Mol Med (Berl). 2005 Jan;83(1):58-63. Shu W et al. Cutaneomucosal venous malformations are linked to the TIE2 mutation in a large Chinese family. Exp Dermatol. 2012 Jun;21(6):456-7. Vikkula M et al. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell. 1996 Dec 27;87(7):1181-90. -
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 849 of the TEK protein (p.Arg849Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with multiple cutaneous and mucosal venous malformations (PMID: 8980225). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9293). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TEK protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects TEK function (PMID: 8980225). For these reasons, this variant has been classified as Pathogenic. -
Multiple cutaneous and mucosal venous malformations Pathogenic:2Other:1
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The TEK c.2545C>T (p.Arg849Trp) variant was identified at an allelic fraction consistent with somatic origin. This variant has been identified in multiple individuals with venous malformations (Vikkula M et al., PMID: 8980225; Wouters V et al., PMID: 19888299; Paolacci S et al., PMID: 33105631). This variant has been reported in the ClinVar database as a pathogenic variant in both a germline and somatic state by multiple submitters (Clinvar Variation ID: 9293). This variant is only observed on 4/1,613,884 alleles in the general population (gnomAD v.4.0.0), indicating it is not a common variant. The TEK c.2545C>T (p.Arg849Trp) variant resides within the kinase domain of TIE2, an endothelium-specific receptor tyrosine kinase that is a critical functional domain (Shewchuk LM et al., PMID: 11080633). Computational predictors indicate that this variant is damaging, evidence that correlates with impact to TEK function. In support of this prediction, functional studies show that overexpression of full-length receptors with this variant in insect cells result in an increased autophosphorylation activity (Vikkula M et al., PMID: 8980225). Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868), the TEK c.2545C>T (p.Arg849Trp) variant is classified as pathogenic. -
Segmental undergrowth associated with venous malformation without capillary component Pathogenic:1
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TEK-related disorder Pathogenic:1
The TEK c.2545C>T variant is predicted to result in the amino acid substitution p.Arg849Trp. This variant was reported in at least 60 individuals in at least 10 unrelated families with venous malformation (Vikkula et al. 1996. PubMed ID: 8980225; Wouters et al. 2009. PubMed ID: 19888299). Functional studies show this variant causes increased receptor hyperphosphorylation and inhibits apoptosis (Wouters et al. 2009. PubMed ID: 19888299; Morris et al. 2004. PubMed ID: 15526080). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -
Abnormal cardiovascular system morphology Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at